[Activity of 9 beta-lactam antibiotics combined with clavulanic acid or sulbactam against the strains of broad-spectrum beta-lactamase (CTX-1) producing Enterobacteriaceae isolated at the Henri Mondor Hospital].
Minimal inhibitory concentrations (MICs) of seven cephalosporins: cefotaxime (CTX), ceftriaxone (CRO), ceftazidime (CAZ), latamoxef (MOX), cefoxitin (FOX), cefotetan (CTT) and CM 40876 (CM), of aztreonam (ATM) and imipenem (IPM) were evaluated by agar dilution with and without 5 mg/l of clavulanic acid (AC) or sulbactam (SB) for 28 strains isolated in 1986 (15 K. pneumoniae, 3. K. oxytoca, 4 E. coli, 4 E. cloacae, 1 E. aerogenes and 1 C. freundii). Comparatively to MICs of sensitive strains and to those of cured variants, MICs of these strains were very increased for CTX, CRO, ATM (mode MIC: 1 mg/l), and CAZ (2); weakly increased for MOX and CTT (0.25), and identical for IMP (0.12-0.25), CM (0.06) and FOX (2-4), except for Enterobacter and Citrobacter (64). Association with AC or SB did not modify MICs of FOX, CM and IMP. For the other antibiotics, MICs were reduced by addition of AC: Klebsiella: 5 log2 for CTX and CRO, 4 for CAZ and ATM, 2 for MOX and CTT; E. coli: 4 log2 for CTX and ATM, 3 for CRO and CAZ, 1 for MOX and CTT; Enterobacter and Citrobacter 2 log2 for CTX, CRO, CAZ and ATM, 1 for MOX and CTT. With SB, decrease of MICs was two to for fold lesser than with AC. AC, and less efficiently SB, restored activity of CTX, CRO, CAZ and ATM on CTX-1 producing Enterobacteriaceae, particularly Klebsiella and E. coli. It was the same for MOX and CTT, weakly affected by this resistance. AC and SB had not effect on FOX, CM and IPM which remained active on these strains.


Emotional Intelligence and Work Perceptions Among Nurse Managers.
Emotional intelligence (EI) refers to a person's ability to acknowledge the feelings of oneself and others, and to control those feelings so as to behave in a socially acceptable manner. We investigated the relationships between the characteristics of EI among nurse managers, and their perceptions of how much their position's roles and responsibilities can be delegated to other staff members. We surveyed 150 nurse managers working at 30 hospitals by using an anonymous questionnaire. The questionnaire consists of basic attributes, EI and work perception. The emotional intelligence scale (EQS) domain scores were analyzed by means of one-way repeated-measures analysis of variance. EQS scores were compared with corresponding averages for working adults in the instructions. The perceived importance of duties of nurse managers was compared between the resulting EQS scores 'High' and 'Low' groups. The analysis population consisted of 105 nurse managers. Their EQS scored higher in all three domains, and with the exception of Altruism for all factor scores than the average for working adults. The perceived importance of the typical duties of nurse managers were compared between the High and Low groups for each EQS domain. Significant differences were observed between nurse managers with High and Low Intrapersonal emotional quotient (EQ) on four tasks. No significant differences were found for any of the responsibilities when nurse managers with High and Low Interpersonal EQ or Situational EQ were compared. The nurse managers' average EQS scores were higher in all areas. The high scores that were exhibited by could be considered desirable qualities for nurse managers. It seemed nurse managers with high scores in intrapersonal EQ struck a good balance between placing importance on EI considerations like managing relationships and creating a comfortable workplace, and management and leadership behaviors like department management and operations and data management.


Black ginseng-enriched Chong-Myung-Tang extracts improve spatial learning behavior in rats and elicit anti-inflammatory effects in vitro.
Chong-Myung-Tang (CMT) extract is widely used in Korea as a traditional herbal tonic for increasing memory capacity in high-school students and also for numerous body ailments since centuries. The use of CMT to improve the learning capacity has been attributed to various plant constituents, especially black ginseng, in it. Therefore, in this study, we have first investigated whether black ginseng-enriched CMT extracts affected spatial learning using the Morris water maze (MWM) test. Their molecular mechanism of action underlying improvement of learning and memory was examined in vitro. We used two types of black ginseng-enriched CMT extracts, designated as CM-1 and CM-2, and evaluated their efficacy in the MWM test for spatial learning behavior and their anti-inflammatory effects in BV2 microglial cells. Our results show that both black ginseng-enriched CMT extracts improved the learning behavior in scopolamine-induced impairment in the water maze test. Moreover, these extracts also inhibited nitric oxide production in BV2 cells, with significant suppression of expression of proinflammatory cytokines, especially inducible nitric oxide synthase, cyclooxygenase-2, and interleukin-1β. The protein expression of mitogen-activated protein kinase and nuclear factor-κB pathway factors was also diminished by black ginseng-enriched CMT extracts, indicating that it not only improves the memory impairment, but also acts a potent anti-inflammatory agent for neuroinflammatory diseases. Our research for the first time provides the scientific evidence that consumption of black ginseng-enriched CMT extract as a brain tonic improves memory impairment. Thus, our study results can be taken as a reference for future neurobehavioral studies.


Evidence from visuomotor adaptation for two partially independent visuomotor systems.
Visual information can specify spatial layout with respect to the observer (egocentric) or with respect to an external frame of reference (allocentric). People can use both of these types of visual spatial information to guide their hands. The question arises if movements based on egocentric and movements based on allocentric visual information comprise 2 independent visuomotor systems. In the experiments reported here, we used visuomotor adaptation to address this question. In an adaptation phase, subjects received distorted-visual feedback about their hand movements (17 degrees rotation and 110% amplitude stretch). In a testing phase (no-visual feedback), we measured how behavior changes in response to the distorted-visual feedback. During adaptation and testing, we used 2 tasks that required processing of either egocentric or allocentric visual information. The results show that behavioral changes are significantly larger when the same task is used during testing and adaptation, compared to when the task is switched. The findings suggest that the human brain employs 2 partially independent visuomotor systems that rely on different types of visual spatial information.


A case of rectal cancer with sternal metastasis as initial presentation.
Colorectal cancer with bone metastasis as initial manifestation is a very rare event. We have reported a case of rectal cancer presenting with sternal metastasis. A 30 year-old man was evaluated due to pain in the sternal area with a bulging mass. History and physical examination did not suggest any specific disease. A radionuclide bone scan revealed increased uptake in the sternal area, right 6th rib, and sacrum. Microscopic examination of a biopsy specimen from the sternum showed metastatic adenocarcinoma. A barium enema and CT scan of the pelvis suggested carcinoma of the upper rectum. Adenocarcinoma of the rectosigmoid junction area was demonstrated by colonoscopic examination with biopsy. He received palliative transverse colostomy for obstruction without further treatment.


Streptomyces lacticiproducens sp. nov., a lactic acid-producing streptomycete isolated from the rhizosphere of tomato plants.
A novel actinomycete, designated strain GIMN4.001(T), was isolated from the rhizosphere of tomato plants grown in Guangzhou, China. The strain produced greyish white aerial mycelia, lactic acid and a large quantity of double diamond-shaped crystals on potato dextrose agar and yeast extract-malt extract agar. The colour of the substrate mycelium was not sensitive to pH. Microscopic observations revealed that strain GIMN4.001(T) produced verticillate chains of cylindrical spores. Chemotaxonomic data confirmed that strain GIMN4.001(T) belonged to the genus Streptomyces. Melanin pigments were not produced. No antibacterial activity was observed against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis or Candida albicans, but inhibitory activity was observed against Penicillium citrinum. 16S rRNA gene sequence analysis revealed that strain GIMN4.001(T) was related most closely to Streptomyces morookaense ATCC 19166(T) (98.9 % similarity) and Streptomyces lavenduligriseus ATCC 13306(T) (98.7 %). Levels of DNA-DNA relatedness between strain GIMN4.001(T) and the type strains of these species were low (14-20 %). Furthermore, strain GIMN4.001(T) could be differentiated from S. morookaense, S. lavenduligriseus and other closely related species of the genus Streptomyces based on morphological, physiological and biochemical characteristics. On the basis of its physiological and molecular properties, strain GIMN4.001(T) is considered to represent a novel species of the genus Streptomyces, for which the name Streptomyces lacticiproducens sp. nov. is proposed. The type strain is GIMN4.001(T) (=CCTCC M208214(T)=NRRL B-24800(T)).


The use of water-soluble contrast enema without pretreatment for the diagnosis of colon disease.
Conventional colonoscopy and barium enema are the main examinations for colonic lesions, but each of them has different limitations according to the condition of the patient. It has been reported that preparations for these examinations also caused complications, such as colonic perforation leading to fatality. To avoid these complications, colonic enema with water-soluble contrast medium (Gatrografin) has been performed as a screening method for those suspected to have obstructive colonic diseases, or those in whom it was difficult to be form colonoscopy and barium enema because of their poor condition. There are few reports about water-soluble contrast enema (WSCE). We retrospectively examined 121 cases of WSCE performed from January 2004 to December 2005 and assessed the acceptability of examination and its ability to detect colonic lesions. We divided our patients into five groups according to the reason for performing WSCE. In all cases, we were able to perform WSCE without complications and assess colonic lesions. In 58 cases, we compared the results of WSCE with those of barium enema or colonoscopy, or both In 8 cases we missed small colonic polyps and erosions, but we missed only one large polyp 3 cm in diameter, which we detected retrospectively. In conclusion, WSCE is safe and useful for the diagnosis of colonic disease, and may be one of the choices of colonic examination especially for those who are suspected to have obstructive colonic diseases or hemorrhagic lesions as well as for those in whom it is difficult to perform barium enema or colonoscopy.


Needs Analysis About Intercultural Communicative Competence Among Undergraduate Tourism Students.
With both the quantitative and qualitative data from 628 responses to a set of questionnaire collected from the undergraduates of three educational institutions in central Vietnam, this study analyzed learners' needs of intercultural communication competence (ICC) related to their studying of English for tourism purposes and future occupations. The methodology used for data analysis including semi-structured interviews, and the questionnaire. The findings showed that the students preferred intercultural language learning activities referring to authentic materials and real-life experience. The results also revealed the participants' great needs of various ICC attitudes and regular tasks in tourism workplaces. Particularly, they had positive attitudes in intercultural communication, and higher needs of tasks for improving discourse and behavioural competences more than other ICC dimensions. The study has implications for tourism learners, educators and related stakeholders to raise their awareness in learning, teaching and developing this long-lasting competence.


[The significance of fiber for swine nutrition with special reference to HCl-treated straw meal].
The term crude fibre according to the Weend analysis method is insufficient for the nutrition of pigs as it does not comprise pentosanes. During the cooking process they are hydrolysed with diluted acid and do not remain in the crude fibre fraction. As stomach HCl can also hydrolyse pentosane (probably in shorter chains), they are well utilized by the microorganisms in the digestive tract (production of volatile fatty acids). Cereal bran and straw meal contain a particularly high quota of pentosanes in their fibre. The fibre fraction of the plant materials fulfills several functions in the digestive tract: absorption of water at the hydroxyl groups of cellulose and hemicellulose (higher absorption capacity of the digesta and improved passage rate); formation of volatile fatty acids (VFA) by the intestinal bacteria due to the fermentation of pentosanes and cellulose (positive influence of VFA on the mucosa of the intestinal walls); absorption of protein decomposition products (including amines) in the cavities of native plant scaffold substances and absorption of aromatic toxic substances (tyramine, phenol, cresol, tryptamine, indole, skatole, histamine etc.) in the lignin by means of VAN DER WAALS forces and further transport of the toxic substances until they are excreted in faeces. HCl treated straw meal is either a mixture of HCl and straw meal at a ratio of 20 kg half concentrated HCl (17% HCl) and 100 kg straw meal with or without heat treatment (steaming for ca. 30 min). The unsteamed product is called HCl straw meal, the steamed product partly hydrolysed straw meal (PHS). 5-10% HCl--straw meal was successfully used in the rearing of piglets after weaning. In addition to the above-mentioned significance of the scaffold substances for the digestive tract, the HCl improved the pH status in the stomach and the upper region of the small intestine. PHS neutralized with CaCO3 (up to pH 6-7) is suitable for breeding sows, boars, young sows and fattening pigs. PSM contains 25% reducing substances (reducing sugars) in the DM and serves the intestinal bacteria in the production of VFA. In the feeding of breeding sows in the phase of gestation 20-30% of the DM intake could be covered by PSM. The number of viable and rearable piglets was significantly higher than after conventional feeding. HCl--SM and PSM also provide advantages with regard to hygiene. They are not congested by fungi and can well be stored without neutralization.


Statement on the safety and efficacy of the feed additive consisting on tragacanth gum for all animal species (Association for International Promotion of Gums).
The additive tragacanth gum is intended to be used as a technological additive (category: technological additive; functional groups: emulsifier, stabiliser, thickener, gelling agent) for all animal species. The Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) assessed the data provided by the applicant in the technical dossier. During the course of the assessment, the need for additional information in order to be able to deliver an opinion on the safety and efficacy of this additive was identified and notified to the applicant. The information requested covered the characterisation and identification, the safety for the target species and the efficacy of the additive. The applicant has failed to provide the additional information. Therefore, considering the data provided in the original dossier and the absence of response from the applicant to the requests from EFSA, the FEEDAP Panel is not in a position to deliver an opinion on the safety and efficacy of the additive tragacanth gum as a technological additive for all animal species.


Alternate methods of framing information about medication side effects: incremental risk versus total risk of occurrence.
Communications of treatment risk, such as medication package inserts, commonly report total rates of adverse reactions (e.g., 4% get heartburn with placebo, 9% with medication). This approach, however, requires mental arithmetic to distinguish the incremental risk caused by medication (here, 5%) from the total post-treatment risk. In two Internet-administered survey experiments (N = 2,012 and 1,393), we tested whether explicitly reporting the incremental risk and framing it as the "additional risk" of complications influenced people's impressions of adverse event risks. Study 1 compared side-by-side displays of total risks against sequential presentations that highlighted the incremental risk, using both text and graphical formats. Results showed that incremental risk formats significantly lowered participants' worry about complications and reduced biases caused by varying the risk denominator. Study 2 unpacked this factor and showed that its effect on both perceived likelihood and worry derives primarily from the incremental risk framing rather than from sequential presentation. Explicitly reporting incremental risk statistics appears to facilitate recognition of how much risk already exists at baseline. Presenting adverse reaction risks in this manner may improve patient comprehension of the effects of treatment decisions and support effective risk communication.


The respiratory local lymph node assay as a tool to study respiratory sensitizers.
The local lymph node assay (LLNA) is used to test the potential of low molecular weight (LMW) compounds to induce sensitization via the skin. In the present study, a respiratory LLNA was developed. Male BALB/c mice were exposed head/nose-only during three consecutive days for 45, 90, 180, or 360 min/day to various LMW allergens. Ear application (skin LLNA) was used as a positive control. Negative controls were exposed to the vehicle. Three days after the last exposure, proliferation was determined in the draining mandibular lymph nodes, and the respiratory tract was examined microscopically. Upon inhalation, the allergens trimellitic anhydride, phthalic anhydride, hexamethylene diisocyanate, toluene diisocyanate, isophorone diisocyanate (IPDI), dinitrochlorobenzene, and oxazolone were positive and showed stimulation indices (SIs) up to 11, whereas trimeric IPDI, formaldehyde, and methyl salicylate were negative (viz. SI < 3). All compounds, except trimeric IPDI, induced histopathological lesions predominantly in the upper respiratory tract. Exposure by inhalation is a realistic approach to test respiratory allergens. However, based on the local toxicity, the dose that can be applied is (generally) much lower than can be achieved by skin application. It is concluded that strong LMW allergens, regardless their immunological nature, besides the skin can also sensitize the body via the respiratory tract. In addition, the contact allergens were as potent as the respiratory allergens, although the potency ranking differed from that in a skin LLNA.


Internalization of the human N-formyl peptide and C5a chemoattractant receptors occurs via clathrin-independent mechanisms.
After stimulation by ligand, most G protein-coupled receptors (GPCRs) undergo rapid phosphorylation, followed by desensitization and internalization. In the case of the N-formyl peptide receptor (FPR), these latter two processing steps have been shown to be entirely dependent on phosphorylation of the receptor's carboxy terminus. We have previously demonstrated that FPR internalization can occur in the absence of receptor desensitization, indicating that FPR desensitization and internalization are regulated differentially. In this study, we have investigated whether human chemoattractant receptors internalize via clathrin-coated pits. Internalization of the FPR transiently expressed in HEK 293 cells was shown to be dependent upon receptor phosphorylation. Despite this, internalization of the FPR, as well as the C5a receptor, was demonstrated to be independent of the actions of arrestin, dynamin, and clathrin. In addition, we utilized fluorescence microscopy to visualize the FPR and beta(2)-adrenergic receptor as they internalized in the same cell, revealing distinct sites of internalization. Last, we found that a nonphosphorylatable mutant of the FPR, unable to internalize, was competent to activate p44/42 MAP kinase. Together, these results demonstrate not only that the FPR internalizes via an arrestin-, dynamin-, and clathrin-independent pathway but also that signal transduction to MAP kinases occurs in an internalization-independent manner.


SELECT: the selenium and vitamin E cancer prevention trial.
Growing evidence suggests that both selenium and vitamin E may reduce the risk of prostate cancer. SELECT is a randomized, prospective, double-blind study designed to determine if selenium and vitamin E can reduce the risk of prostate cancer among healthy men. The preclinical and epidemiologic evidence regarding chemoprevention with selenium and vitamin E were reviewed. Secondary analyses from randomized trials of both agents were included in the analysis. Data from these analyses as well as evidence from the Prostate Cancer Prevention Trial were used to develop the schema of SELECT. Preclinical, epidemiologic, and Phase III data suggest that both selenium and vitamin E have potential efficacy in prostate cancer prevention. The experience of the Prostate Cancer Prevention Trial and the rapid accrual of SELECT during its first year demonstrate the interest and dedication of healthy men to long-term studies of cancer prevention. A total of 32,400 men are planned to be randomized in SELECT. SELECT is the second large-scale study of chemoprevention for prostate cancer. Enrollment began in 2001 with final results anticipated in 2013.


Safety/Efficacy of New Topical Silicone Formulation with Selective Growth Factors for Treating Striae Distensae.
Striae distensae (SD) are linear dermal scars that arise from progressive stretching or tearing of the dermal layer. This study tests the safety and efficacy of a topical formulation of silicone-based scar cream containing selective synthetic recombinant human growth factors, hyaluronic acid, and vitamin C to improve overall appearance and texture of SD. Twenty-two subjects with SD alba were recruited and randomized to apply the topical formula to half of their SD laterally twice a day for 1 month. Patient surveys were obtained at 1 month for overall appearance, texture, and tolerability. Three-dimensional imaging was obtained at baseline and at 1 month and submitted to independent evaluators for grading on overall appearance. Subjects reported improved texture and appearance in 86.4% of SD. Subjects reported 100% of untreated SD to have no change in overall appearance or texture. 90.9% of subjects reported no tolerability issues. 9.1% of the treated group reported mild issues such as slight itching or redness the first day of application, which subsided in 2 days for all patients. Independent evaluators indicated improvement in 72.7% of SD in comparison to improvement in 36.3% of untreated SD. This study demonstrates that the investigated topical formulation is safe and effective to use for SD.


Building a consensus for expanding health coverage.
Despite a flourishing economy and recent growth in employment-based health coverage, forty-three million Americans remain uninsured. Extending coverage to the uninsured is not an intractable public policy problem but could be addressed if the various health care stakeholders could only find common ground. We argue that to win broad-based support from across the ideological and political spectra, a meaningful proposal should achieve a balance between public- and private-sector approaches, focus attention on those who are most in need of assistance (low-income workers), and build on systems that work today. With the aim of pulling together a political coalition, we present a proposal specific enough to attract support but whose details will arise later, in the context of the legislative process.


Imaging, Genetic, and Demographic Factors Associated With Conversion to Neovascular Age-Related Macular Degeneration: Secondary Analysis of a Randomized Clinical Trial.
Risk factors associated with the development of neovascular age-related macular degeneration (AMD) have been identified. However, population size and methods to integrate imaging, genetic, and demographic factors associated with conversion to neovascular AMD are limited, specifically when treatment is administered in 1 eye. To determine the imaging, genetic, and demographic factors associated with conversion from nonneovascular to neovascular AMD in fellow eyes. This post hoc secondary analysis of the 24-month phase 3 multicenter, double-masked, active treatment-controlled HARBOR trial included 686 fellow eyes with nonneovascular AMD at baseline. Imaging features describing the presence, number, extent, density, and relative reflectivity of drusen were automatically extracted from spectral-domain optical coherence tomography scans. Genetic analysis included 34 single-nucleotide polymorphisms. Least absolute shrinkage and selection operator regression was performed to narrow imaging features. Survival analysis and Cox proportional hazards regression were performed to determine the association of the selected imaging features and genetic and demographic factors with conversion to neovascular AMD. Data were collected from November 2016 through October 2017 and analyzed from October 2017 through October 2018. Nonneovascular AMD in the fellow eye. Features associated with conversion to neovascular AMD. Hazard ratios (HRs) and their 95% CIs were calculated. Among the 686 fellow eyes included in the analysis (406 [59.2%] women; mean [SD] age, 78.12 [8.28] years), 154 (22.4%) converted to neovascular AMD. Female sex was significantly associated with conversion to neovascular AMD (HR, 1.57; 95% CI, 1.11-2.20; P = .009). After controlling for demographic and treatment effects, drusen area within 3 mm of the fovea (HR, 1.45; 95% CI, 1.24-1.69; HR for 1-SD increase, 1.36 [95% CI, 1.20-1.54]) and mean drusen reflectivity (HR, 3.97; 95% CI, 1.11-14.18; HR for 1-SD increase, 1.32 [95% CI, 1.02-1.71]) were significantly associated with conversion to neovascular AMD. In addition, 1 genetic variant (rs61941274) was found to be associated with conversion to neovascular AMD. Two imaging features (total en face area of drusen restricted to a circular area 3 mm from the fovea and mean drusen reflectivity) and 1 genetic variant (ACAD10 locus) were associated with conversion to neovascular AMD. Drusen characteristics may be associated with conversion to neovascular AMD despite treatment in 1 eye. ClinicalTrials.gov identifier: NCT00891735.


[Daughter DNA synthesis in UV-resistant and UV-sensitive Chinese hamster clones cells under UV irradiation].
By means of ultracentrifugation in alkaline sucrose gradients it has been shown that the size of DNA fragments synthesized in Chinese hamster cells of UV-sensitive clone (CHS-1) after exposure to UV light was equal to the distance between pyrimidine dimers in the parental DNA determined using endonuclease of Micrococcus luteus. With the UV-resistant clone (V-79), the length of fragments of the newly synthesized DNA was much longer than that between pyrimidine dimers in the parental DNA. The data obtained support the model according which DNA synthesis on the UV-irradiated template gives rise to gaps opposite to pyrimidine dimers.


Fertility preservation methods in young women with systemic lupus erythematosus prior to cytotoxic therapy: experiences from the FertiPROTEKT network.
Despite new treatment options, some patients with systemic lupus erythematosus (SLE) need to be treated with the cytotoxic agent cyclophosphamide (CYC). Unlike malignant disease, there are no recommendations for ovarian protection in SLE. The clinical experience of the FertiPROTEKT network as well as recommendations after literature review will be presented in this paper. Retrospective analyses of counselling and treatment data from the FertiPROTEKT register with special respect to SLE patients under 40 years prior to planned CYC treatment. A total of 2836 patients were advised prior to cytotoxic treatment in one of the FertiPROTEKT centres during January 2007 to November 2011. Of those, 68 patients (mean age 25 +/- 6.07 years) were counselled for severe SLE. Only five women did not make use of a fertility preservation method. Sixty-three patients (92.6%) decided in favour of a fertility preservation method. The largest proportion (91.2%) opted for treatment with a GnRH analogue. Ovarian tissue removal for cryoconservation was performed in 16 patients (25%). Stimulation therapy for cryoconservation of fertilized egg cells was performed in three patients (4.4%). When counselling patients with SLE for fertility preservation one has to be aware of the disease-specific risks. According to the literature, a safe and effective option in SLE up to now has been the use of a GnRH analogue. Cryoconservation of ovarian tissue must still be seen as an experimental treatment, but as data on removal, cryoconservation, retransplantation and pregnancies are steadily rising, this presents a promising option for young SLE patients. Cryoconservation of oocytes must be very critically evaluated due to the need for a stimulation therapy and should only be performed after particular consideration of the individual risks.


Growth hormone therapy in noonan syndrome.
Noonan syndrome (NS) is an autosomal dominant disorder that can be difficult to diagnose. Growth retardation is a consistent feature, however, and although children are not typically growth hormone (GH) deficient, a minority may have suboptimal GH levels. An ongoing multicentre study examining the safety and efficacy of GH therapy in NS showed increases in height standard deviation scores (SDS; p < 0. 0001) and height velocity (p < 0.0001) after 12 months of GH at pharmacological doses. There was no increase in mean maximal cardiac left ventricular wall thickness during the 12-month treatment period. Long-term follow-up data covering 3 years of GH therapy showed sustained increases in height SDS and height velocity compared with baseline (p < 0.02). Further large and appropriately controlled studies of high-quality design are essential to further our understanding of NS and to establish the long-term safety and efficacy of GH.


Combined use of immunoassay and two-dimensional liquid chromatography mass spectrometry for the detection and identification of metabolites from biotherapeutic pharmacokinetic samples.
Peptides and monoclonal antibodies have both emerged as important therapeutic modalities, but each has challenges which limit their use. Non-recombinant chemical conjugation of peptides onto antibodies has the potential to minimize or eliminate altogether many of these limitations. Once such approach, pioneered by CovX has created the possibility for rapid stoichiometric fusion of pharmacophores to a single antibody platform. These molecules, called CovX-Bodies, maintain both the pharmacologic properties of a given peptide and the pharmacokinetic properties of a monoclonal antibody. The result is a new class of molecules wherein each component contributes desirable traits. In this paper, we demonstrate the use of immunoassay and two-dimensional liquid chromatography mass spectrometry (2DLC/MS) in combination to investigate the antibody conjugates of Glucagon-like peptide-1 (GLP-1) and analogs for intact protein metabolite identification directly from mouse serum. The information gained from combining these approaches has helped guide and expedite the optimization of our drug product development efforts.


[Depressive and anxiety symptoms in a community sample of young adults and correlation with help-seeking behavior].
To evaluate: (i) self-perceived stress, depressive and anxiety symptoms in a community sample of young adults; (ii) which elements have most impact on the development of mental disease; (iii) if high levels of mental disease are related to help-seeking behavior. The study was carried out on a sample of 1660 university students. The evaluation of the perceived stress was conducted using the Stress-Related Vulnerability Scale (SVS), the evaluation of depressive and anxiety symptoms with Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI). A descriptive analysis of all the data collected was carried out and the principal links between variables and level of mental disease were detected. Finally the reasons for the failure to seek help were investigated. Mean scores of BDI-II and BAI were respectively 10.9 (sigma = 8.3) and 11.4 (sigma = 9.4) and about 4% of the sample showed a pathological level of stress with the SVS. Female sex, non resident status and conflictual family climate were found to be more related with more severe anxious and depressive symptoms. Moreover, the latter ones were found to be strongly related with help-seeking behavior. In this sample mental disease associated with distress show a significant percentage. Higher level of anxiety and depressive symptoms are more related to perceived need for help and help-seeking behavior. Nevertheless the level of unexpressed help-seeking turn out to be high for multiple reason.


Ferroptosis resistance in cancer: recent advances and future perspectives.
Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death and has been implicated in the occurrence and development of various diseases, including heart disease, nervous system diseases and cancer. Ferroptosis induction recently emerged as an attractive strategy for cancer therapy. Ferroptosis has become a potential target for intervention in these diseases or injuries in relevant preclinical models. This review summarizes recent progress on the mechanisms of ferroptosis resistance in cancer, highlights redox status and metabolism's role in it. Combination therapy for ferroptosis has great potential in cancer treatment, especially malignant tumors that are resistant to conventional therapies. This review will lead us to have a comprehensive understanding of the future exploration of ferroptosis and cancer therapy. A deeper understanding of the relationship between ferroptosis resistance and metabolism reprogramming may provide new strategies for tumor treatment and drug development based on ferroptosis.


Whole-body cryostimulation in kayaker women: a study of the effect of cryogenic temperatures on oxidative stress after the exercise.
The aim of this study was to determine the effect of whole-body cryostimulation on the activity of selected antioxidant enzymes and the concentration of lipid peroxidation products in kayaker women in the course of training. The study was performed on the group of 9 kayaker women, who underwent two training cycles: one typical ten-day training cycle and the another ten-day cycle preceded by cryostimulation sessions twice a day. The activity of antioxidant enzymes was assayed in erythrocytes, while the concentration of lipid peroxidation products was measured both in erythrocytes and in blood plasma. A statistically significant increase in superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity in erythrocytes and in concentration of conjugated dienes (CD) in blood plasma and erythrocytes and thiobarbituric acid reactive substances (TBARS) in plasma was revealed in kayaker women after the first six days of training without cryostimulation. Comparing two performed training cycles, after the first six days of training preceded by cryostimulation lower SOD and GPx activity in erythrocytes was detected, as well as lower CD levels in blood plasma and erythrocytes and lower TBARS concentration in blood plasma of kayaker women than after the six days of training without cryostimulation. Whole-body cryostimulation improves the antioxidant capacity of organism exposed to intense exercise. Brief application of cryogenic temperatures is likely related to the activation of adaptive homeostatic mechanisms in accordance with the hormetic dose-response model.


Investigation of ammonia-induced lethal toxicity toward ion regulation in zebrafish embryos.
Ammonia is an environmental pollutant that is toxic to all aquatic animals. However, the mechanism of ammonia toxicity toward the ion regulatory function of early-stage fish has not been fully documented. We addressed this issue using zebrafish embryos as a model. We hypothesized that ammonia might impair ion regulation by inducing oxidative stress, mitochondrial dysfunction, and cell death of epidermal ionocytes and keratinocytes in zebrafish embryos. After exposure to various concentrations (10- 30 mM) of NH4Cl for 96 h, mortality increased up to 50 % and 100 % at 25 and 30 mM, respectively. Whole-embryo sodium, potassium, and calcium contents decreased at ≥10 mM, suggesting dysfunction of ion regulation. Numbers of H+-ATPase-rich (HR) cells and Na+/K+-ATPase-rich (NaR) cells (two ionocyte subtypes) were not significantly altered at 15 or 20 mM, while the mitochondrial abundance significantly decreased and reactive oxygen species (ROS) levels significantly increased in ionocytes. Moreover, caspase-3-dependent apoptosis was found in epidermal keratinocytes. Whole-embryo transcript levels of several genes involved in ion regulation, antioxidation, and apoptosis were upregulated after ammonia exposure. In conclusion, ammonia exposure was shown to induce oxidative stress and mitochondrial dysfunction in ionocytes and apoptosis in keratinocytes, thereby impairing ion regulation and ultimately leading to the death of zebrafish embryos.


Feasibility of a combined camp approach for vector control together with active case detection of visceral leishmaniasis, post kala-azar dermal leishmaniasis, tuberculosis, leprosy and malaria in Bangladesh, India and Nepal: an exploratory study.
We assessed the feasibility and results of active case detection (ACD) of visceral leishmaniasis (VL), post kala-azar dermal leishmaniasis (PKDL) and other febrile diseases as well as of bednet impregnation for vector control. Fever camps were organized and analyzed in twelve VL endemic villages in Bangladesh, India, and Nepal. VL, PKDL, tuberculosis, malaria and leprosy were screened among the febrile patients attending the camps, and existing bednets were impregnated with a slow release insecticide. Among the camp attendees one new VL case and two PKDL cases were detected in Bangladesh and one VL case in Nepal. Among suspected tuberculosis cases two were positive in India but none in the other countries. In India, two leprosy cases were found. No malaria cases were detected. Bednet impregnation coverage during fever camps was more than 80% in the three countries. Bednet impregnation led to a reduction of sandfly densities after 2 weeks by 86% and 32%, and after 4 weeks by 95% and 12% in India and Nepal respectively. The additional costs for the control programmes seem to be reasonable. It is feasible to combine ACD camps for VL and PKDL along with other febrile diseases, and vector control with bednet impregnation.


A randomized trial of two print interventions to increase colon cancer screening among first-degree relatives.
First-degree relatives (FDRs) of people diagnosed with colorectal cancer (CRC) have a two- to threefold increased risk of developing the same disease. Tailored print interventions based on behavior change theories have demonstrated considerable promise in facilitating health-promoting behaviors. This study compared the impact of two mailed print interventions on CRC screening outcomes among FDRs. This randomized trial compared effects of two mailed print interventions--one tailored and one nontailored--on participation in CRC screening among FDRs of CRC survivors. Data collected via phone interviews from 140 FDRs at baseline, 1 week post-intervention, and 3 months post-intervention. At 3 months, both the tailored and nontailored interventions yielded modest but statistically insignificant increases in adherence to any CRC screening test (14% vs. 21%, respectively; p=0.30). While there were no main effects for tailored versus nontailored interventions, there were significant interactions that showed that the tailored print intervention had significantly greater effects on forward stage movement for CRC screening depending on stage of adoption at baseline, race, and objective CRC risk. Receipt of the tailored intervention was 2.5 times more likely to move baseline precontemplators and contemplators forward in stage of adoption for colonoscopy (95% CI: 1.10-5.68) and was three times more likely to move Caucasians forward in stage of adoption for FOBT (95% CI: 1.00-9.07). In addition, the tailored intervention was 7.7 times more likely to move people at average risk forward in stage of adoption for colonoscopy (95% CI: 1.25-47.75). The tailored print intervention was more effective at moving Caucasians, those in precontemplation and contemplation at baseline, and those at average risk forward in their stage of adoption for CRC screening. Both tailored and nontailored print interventions showed moderate effects for increasing CRC screening participation. Tailored print interventions may be more effective for certain subgroups.


Interaction between transmembrane domains five and six of the alpha -factor receptor.
The alpha-factor pheromone receptor (STE2) activates a G protein signal pathway that induces conjugation of the yeast Saccharomyces cerevisiae. Previous studies implicated the third intracellular loop of this receptor in G protein activation. Therefore, the roles of transmembrane domains five and six (TMD5 and -6) that bracket the third intracellular loop were analyzed by scanning mutagenesis in which each residue was substituted with cysteine. Out of 42 mutants examined, four constitutive mutants and two strong loss-of-function mutants were identified. Double mutants combining Cys substitutions in TMD5 and TMD6 gave a broader range of phenotypes. Interestingly, a V223C mutation in TMD5 caused constitutive activity when combined with the L247C, L248C, or S251C mutations in TMD6. Also, the L226C mutation in TMD5 caused constitutive activity when combined with either the M250C or S251C mutations in TMD6. The residues affected by these mutations are predicted to fall on one side of their respective helices, suggesting that they may interact. In support of this, cysteines substituted at position 223 in TMD5 and position 247 in TMD6 formed a disulfide bond, providing the first direct evidence of an interaction between these transmembrane domains in the alpha-factor receptor. Altogether, these results identify an important region of interaction between conserved hydrophobic regions at the base of TMD5 and TMD6 that is required for the proper regulation of receptor signaling.


Disruption of entire Cables2 locus leads to embryonic lethality by diminished Rps21 gene expression and enhanced p53 pathway.
In vivo function of CDK5 and Abl enzyme substrate 2 (Cables2), belonging to the Cables protein family, is unknown. Here, we found that targeted disruption of the entire Cables2 locus (Cables2d) caused growth retardation and enhanced apoptosis at the gastrulation stage and then induced embryonic lethality in mice. Comparative transcriptome analysis revealed disruption of Cables2, 50% down-regulation of Rps21 abutting on the Cables2 locus, and up-regulation of p53-target genes in Cables2d gastrulas. We further revealed the lethality phenotype in Rps21-deleted mice and unexpectedly, the exon 1-deleted Cables2 mice survived. Interestingly, chimeric mice derived from Cables2d ESCs carrying exogenous Cables2 and tetraploid wild-type embryo overcame gastrulation. These results suggest that the diminished expression of Rps21 and the completed lack of Cables2 expression are intricately involved in the embryonic lethality via the p53 pathway. This study sheds light on the importance of Cables2 locus in mouse embryonic development.


Mapping practice population and morbidity with a computer.
A method of dividing a map of the practice area into a grid based on postcode locations is described. The distribution of the practice population may thus be shown graphically and trends observed. The geographical incidence and prevalence of morbidity may also be charted and variations of statistical significance determined. This is a practical tool that will have greater potential as information technology in general practice develops.


Design of a System of Systems (SoS) for the Interoperability of Non-Invasive Sensors for the Care of Older People.
We propose the design of a system of systems (SoS) called Seniors Guardian as an integrated environment for healthcare monitoring, in which several non-invasive sensors coexist to monitor falls, nocturia, perseverant behaviors, air quality (carbon monoxide), humidity, and temperature in real time. The modular architecture also allows the integration of new components. This research adheres to the use of Internet of Things to develop ambient assisted living in smart homes.


Aerosol delivery of DNA/liposomes to the lung for cystic fibrosis gene therapy.
Abstract Lung gene therapy is being evaluated for a range of acute and chronic diseases, including cystic fibrosis (CF). As these therapies approach clinical realization, it is becoming increasingly clear that the ability to efficiently deliver gene transfer agents (GTAs) to target cell populations within the lung may prove just as critical as the gene therapy formulation itself in terms of generating positive clinical outcomes. Key to the success of any aerosol gene therapy is the interaction between the GTA and nebulization device. We evaluated the effects of aerosolization on our preferred formulation, plasmid DNA (pDNA) complexed with the cationic liposome GL67A (pDNA/GL67A) using commercially available nebulizer devices. The relatively high viscosity (6.3±0.1 cP) and particulate nature of pDNA/GL67A formulations hindered stable aerosol generation in ultrasonic and vibrating mesh nebulizers but was not problematic in the jet nebulizers tested. Aerosol size characteristics varied significantly between devices, but the AeroEclipse II nebulizer operating at 50 psi generated stable pDNA/GL67A aerosols suitable for delivery to the CF lung (mass median aerodynamic diameter 3.4±0.1 μm). Importantly, biological function of pDNA/GL67A formulations was retained after nebulization, and although aerosol delivery rate was lower than that of other devices (0.17±0.01 ml/min), the breath-actuated AeroEclipse II nebulizer generated aerosol only during the inspiratory phase and as such was more efficient than other devices with 83±3% of generated aerosol available for patient inhalation. On the basis of these results, we have selected the AeroEclipse II nebulizer for the delivery of pDNA/GL67A formulations to the lungs of CF patients as part of phase IIa/b clinical studies.


Comparison of four clinical specimen types for detection of influenza A and B viruses by optical immunoassay (FLU OIA test) and cell culture methods.
Although laboratory diagnosis of respiratory viruses has been widely studied, there is a relative insufficiency of literature examining the impact of specimen type on the laboratory diagnosis of influenza A and B. In a clinical study comparing the FLU OIA test with 14-day cell culture, clinical specimens from nasopharyngeal swabs, throat swabs, nasal aspirates, and sputum were obtained from patients experiencing influenza-like symptoms. A total of 404 clinical specimens were collected from 184 patients. Patients were defined as influenza positive if the viral culture of a specimen from any sample site was positive. Patients were defined as influenza negative if the viral cultures of specimens from all sample sites were negative. By this gold standard, culture and FLU OIA test results for each sample type were compared. For each of the four specimen types, the viral culture and FLU OIA test demonstrated equal abilities to detect the presence of influenza A or B virus or viral antigen. Sputum and nasal aspirate samples were the most predictive of influenza virus infection. Throat swabs were the least predictive of influenza virus infection, with both tests failing to detect influenza virus in nearly 50% of the throat samples studied.


Drug-eluting balloons in the treatment of de-novo coronary lesions: a meta-analysis of randomized-controlled trials.
The aim of this meta-analysis was to evaluate the efficacy of drug-eluting balloons (DEBs) plus bare-metal stents (BMS) for the treatment of de-novo coronary lesions. Eleven trials involving 1279 patients were included in this study. The main endpoints were as follows: late lumen loss (LLL), binary restenosis, stent thrombosis (ST), and major adverse cardiovascular events (MACEs). The definition of MACEs was a composite of death, myocardial infarction (MI), and target lesion revascularization (TLR). Compared with BMS alone, DEB plus BMS showed a lower risk for LLL (P=0.007) and MACEs (P=0.010). There were no significant differences in binary restenosis (P=0.212), ST (P=0.199), death (P=0.141), MI (P=0.439), and TLR (P=0.340). Compared with drug-eluting stents (DES), DEB plus BMS could increase the risk of LLL (P=0.002) and MACEs (P=0.026). The risks of binary restenosis (P=0.113), ST (P=0.832), death (P=0.115), MI (P=0.831), and TLR (P=0.111) were similar between DEB plus BMS and DES. DEB plus BMS was better than BMS alone in reducing LLL and MACEs, especially when dilatation was performed after stenting for de-novo coronary lesions, but it was inferior to DES. Therefore, the treatment strategy with DEB plus BMS should not be recommended for de-novo coronary lesions, except for patients who have contraindications for DES.


Screening a Protein Array with Synthetic Biotinylated Inorganic Polyphosphate To Define the Human PolyP-ome.
Phenotypes are established by tight regulation on protein functions. This regulation can be mediated allosterically, through protein binding, and covalently, through post-translational modification (PTM). The integration of an ever-increasing number of PTMs into regulatory networks enables and defines the proteome complexity. Protein PTMs can occur enzymatically and nonenzymatically. Polyphosphorylation, which is a recently discovered PTM that belongs to the latter category, is the covalent attachment of the linear ortho-phosphate polymer called inorganic polyphosphate (polyP) to lysine residues. PolyP, which is ubiquitously present in nature, is also known to allosterically control protein function. To date, lack of reagents has prevented the systematic analysis of proteins covalently and/or allosterically associated with polyP. Here, we report on the chemical synthesis of biotin-modified monodisperse short-chain polyP (bio-polyP8-bio) and its subsequent use to screen a human proteome array to identify proteins that associate with polyP, thereby starting to define the human polyP-ome.


PIF1 promotes phytochrome-regulated growth under photoperiodic conditions in Arabidopsis together with PIF3, PIF4, and PIF5.
Seedlings growing under diurnal conditions display maximal growth at the end of the night in short-day (SD) photoperiods. Current evidence indicates that this behaviour involves the action of PHYTOCHROME-INTERACTING FACTOR 3 (PIF3) together with PIF4 and PIF5, through direct regulation of growth-related genes at dawn coinciding with a PIF3 accumulation peak generated by phytochrome-imposed oscillations in protein abundance. Here, to assess how alterations in PIF3 levels impact seedling growth, the night-specific accumulation of PIF3 was modulated by releasing SD-grown seedlings into continuous light, or by exposing them to a phytochrome-inactivating end-of-day far-red pulse (EOD-FRp). The data show a strong direct correlation between PIF3 accumulation, PIF3-regulated induction of growth-related genes, and hypocotyl elongation, and suggest that growth promotion in SD conditions involves factors other than PIF3, PIF4, and PIF5. Using a pif1 mutant, evidence is provided that PIF1 also contributes to inducing hypocotyl elongation during the dark period under diurnal conditions. PIF1 displayed constitutive transcript levels in SD conditions, suggesting that phytochrome-imposed oscillations in PIF1 protein abundance determine its accumulation and action during the night, similar to PIF3 and in contrast to PIF4 and PIF5, which oscillate diurnally due to a combination of circadian clock-regulated transcription and light control of protein accumulation. Furthermore, using single and higher order pif mutants, the relative contribution of each member of the PIF quartet to the regulation of morphogenesis and the expression of selected growth marker genes under SD conditions, or under SD conditions supplemented with an EOD-FRp, is defined. Collectively, the data indicate that PIF1, PIF3, PIF4, and PIF5 act together to promote and optimize growth under photoperiodic conditions.


[Mental health and the nurse's work].
The study aimed at knowing, with three nurses from a hospital in Pelotas, Brazil, how they perceive their mental health in relation to their work and which factors cause pleasure/suffering in their job. It relates to a descriptive, analytical research within a qualitative approach. The data were collected by means of a semi-structured interview. The results were presented through central themes such as: pleasure manifestations, suffering and the mental health upon working. Knowing the factors that propitiate mental health, pleasure, suffering at work opens up possibilities of changes for nursing activity, contributing to the struggle for more human and fair work labor issues.


Impact of Tumor and Immunological Heterogeneity on the Anti-Cancer Immune Response.
Metastatic tumors are the primary cause of cancer-related mortality. In recent years, interest in the immunologic control of malignancy has helped establish escape from immunosurveillance as a critical requirement for incipient metastases. Our improved understanding of the immune system's interactions with cancer cells has led to major therapeutic advances but has also unraveled a previously unsuspected level of complexity. This review will discuss the vast spatial and functional heterogeneity in the tumor-infiltrating immune system, with particular focus on natural killer (NK) cells, as well as the impact of tumor cell-specific factors, such as secretome composition, receptor-ligand repertoire, and neoantigen diversity, which can further drive immunological heterogeneity. We emphasize how tumor and immunological heterogeneity may undermine the efficacy of T-cell directed immunotherapies and explore the potential of NK cells to be harnessed to circumvent these limitations.


Parasitism may enhance rather than reduce the predatory impact of an invader.
Invasive species can have profound impacts on communities and it is increasingly recognized that such effects may be mediated by parasitism. The 'enemy release' hypothesis posits that invaders may be successful and have high impacts owing to escape from parasitism. Alternatively, we hypothesize that parasites may increase host feeding rates and hence parasitized invaders may have increased community impacts. Here, we investigate the influence of parasitism on the predatory impact of the invasive freshwater amphipod Gammarus pulex. Up to 70 per cent of individuals are infected with the acanthocephalan parasite Echinorhynchus truttae, but parasitized individuals were no different in body condition to those unparasitized. Parasitized individuals consumed significantly more prey (Asellus aquaticus; Isopoda) than did unparasitized individuals. Both parasitized and unparasitized individuals displayed Type-II functional responses (FRs), with the FR for parasitized individuals rising more steeply, with a higher asymptote, compared with unparasitized individuals. While the parasite reduced the fitness of individual females, we predict a minor effect on population recruitment because of low parasite prevalence in the peak reproductive period. The parasite thus has a large per capita effect on predatory rate but a low population fitness effect, and thus may enhance rather than reduce the impact of this invader.


Biochemistry of the bacterial catabolism of aromatic compounds in anaerobic environments.
Methods of aerobic degradation of aromatic compounds in the biosphere are well understood, but it is only relatively recently that it has been shown how some bacteria can also degrade these substrates in the absence of molecular oxygen. This occurs by photometabolism (Athiorhodaceae), nitrate respiration (Pseudomonas and Moraxella sp.) and methanogenic fermentation (a consortium) in which the benzene nucleus is first reduced and then cleaved by hydrolysis to yield aliphatic acids for cell growth. These methods may be used by microbial communities to catabolise man-made pollutants.


Sexuality counseling for adults with disabilities: a module for an occupational therapy curriculum.
Occupational therapists, as well as other rehabilitation professionals, are aware that sexuality counseling is an important aspect of rehabilitation. However, occupational therapists have limited resources within their profession for training in this area. This paper describes the development, philosophy, goals, objectives, and format of the module "Sexuality and Disability" offered to occupational therapy students at Tufts University. Evaluations from the 288 students who have taken this module to date indicate that all students considered the module a pertinent part of their academic program. Other occupational therapy schools might wish to incorporate a similar component into their curricula to expand the resources within the profession for training in sexuality counseling.


How Media Stories in Low- and Middle-Income Countries Discussed the U.S. Food and Drug Administration's Modified Risk Tobacco Product Order for IQOS.
In 2020, the U.S. Food and Drug Administration authorized the marketing of IQOS as a modified risk tobacco product (MRTP) with reduced exposure information (reduces exposure to harmful chemicals compared to cigarettes) but prohibited Philip Morris International from making reduced risk claims (reduces risk of disease compared to cigarettes). We aimed to assess how news media in low- and middle-income countries (LMICs) discussed this authorization and whether articles discussed IQOS as a reduced exposure versus reduced risk product. News articles published between July 7, 2020 and January 7, 2021 were obtained by searching Tobacco Watcher (www.tobaccowatcher.org), a surveillance platform for tobacco-related news. Articles were eligible if they were published in an LMIC and mentioned the IQOS MRTP order. Non-English language articles were professionally translated. Articles were double coded to identify country of origin, reduced risk and reduced exposure language, discussions of potential impacts of the authorization on regulations in LMICs, and quotes from tobacco industry and public health stakeholders. We identified 50 eligible articles published in 20 LMICs. Twenty-six (52%) and 40 (80%) included reduced risk and reduced exposure language, respectively. Twenty-two (44%) discussed potential impacts of the MRTP order on regulations in LMICs. Thirty (60%) included quotes from tobacco industry representatives, 6 (12%) included quotes from public health or medical professionals, and 2 (4%) included both. News articles in LMICs frequently misreported the MRTP order by using reduced risk language. The authorization is potentially being used to shape perspectives on tobacco regulations in LMICs. Tobacco control experts need to more frequently share their perspectives with the news media. News articles from LMICs frequently misrepresented the IQOS MRTP order by using reduced risk language (reduces harm compared to cigarettes) rather than only using reduced exposure language (reduces exposure to harmful chemicals compared to cigarettes). Many articles referred to IQOS as a "better alternative" to cigarettes without specifically referencing reduced risk. Few articles included perspectives from public health or medical professionals, while most included tobacco industry quotes, suggesting that tobacco control experts need to more frequently engage with the news media. These findings also highlight how the U.S. FDA's actions can potentially shape perspectives on tobacco product regulations in LMICs.


Blood and liver telomere length, mitochondrial DNA copy number, and hepatic gene expression of mitochondrial dynamics in mid-lactation cows supplemented with L-carnitine under systemic inflammation.
The current study was conducted to examine the effect of L-carnitine supplementation on telomere length and mitochondrial DNA copy number (mtDNAcn) per cell in mid-lactation cows challenged by lipopolysaccharide (LPS) in blood and liver. The mRNA abundance of 31 genes related to inflammation, oxidative stress, and the corresponding stress response mechanisms, the mitochondrial quality control and the protein import system, as well as the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, were assessed using microfluidics integrated fluidic circuit chips (96.96 dynamic arrays). Besides comparing the responses in cows with or without L-carnitine, our objectives were to characterize the oxidative and inflammatory status by assessing the circulating concentration of lactoferrin (Lf), haptoglobin (Hp), fibrinogen, derivates of reactive oxygen metabolites (dROM), and arylesterase activity (AEA), and to extend the measurement of Lf and Hp to milk. Pluriparous Holstein cows were assigned to either a control group (CON, n = 26) or an L-carnitine supplemented group (CAR; 25 g L-carnitine/cow/d; d 42 ante partum to d 126 postpartum (pp), n = 27). On d 111 pp, each cow was injected intravenously with LPS (Escherichia coli O111: B4, 0.5 µg/kg). The mRNA abundance was examined in liver biopsies of d -11 and +1 relative to LPS administration. Plasma and milk samples were frequently collected before and after the challenge. After LPS administration, circulating plasma fibrinogen and serum dROM concentrations increased, whereas AEA decreased. Moreover, serum P4 initially increased by 3 h after LPS administration and declined thereafter irrespective of grouping. The Lf concentrations increased in both groups after LPS administration, with the CAR group showing greater concentrations in serum and milk than the CON group. After LPS administration, telomere length in blood increased, whereas mtDNAcn per cell decreased; however, both remained unaffected in liver. For mitochondrial protein import genes, the hepatic mRNA abundance of the translocase of the mitochondrial inner membrane (TIM)-17B was increased in CAR cows. Moreover, TIM23 increased in both groups after LPS administration. Regarding the mRNA abundance of genes related to stress response mechanisms, 7 out of 14 genes showed group × time interactions, indicating a (local) protective effect due to the dietary L-carnitine supplementation against oxidative stress in mid-lactating dairy cows. For mtDNAcn and telomere length, the effects of the LPS-induced inflammation were more pronounced than the dietary supplementation of L-carnitine. Dietary L-carnitine supplementation affected the response to LPS primarily by altering mitochondrial dynamics. Regarding mRNA abundance of genes related to the mitochondrial protein import system, the inner mitochondrial membrane translocase (TIM complex) seemed to be more sensitive to dietary L-carnitine than the outer mitochondrial membrane translocase (TOM complex).


Effectiveness of the Analgesia Nociception Index Monitoring in Patients Who Undergo Colonoscopy with Sedo-Analgesia.
The objective of this study was to improve the patient comfort and safety during procedures done under anaesthesia and sedation. The analgesia nociception index (ANI) noninvasively provides information on the nociception-antinociception balance, and it can be used to assess analgesia objectively. We aimed to compare the effects of analgesia management with conventional methods and with ANI monitoring on total opioid consumption, sedation and analgesia levels in patients who underwent colonoscopy using sedo-analgesia. Adult patients (n=102), scheduled for procedural sedation, were prospectively analysed. After the induction with propofol and ketamine, infusions of propofol (2 mg kg-1 h-1) and remifentanil (0.05 mcg kg-1 min-1) were started. In Group A, remifentanil infusions were titrated to maintain the ANI value between 50 and 70, whereas in Group C, analgesic requirements were met according to the attending anaesthetist's intention. The heart rate, blood pressure, respiratory rate, SpO2, BIS, Numeric Rating Scale (NRS) and Ramsay Sedation Scale were monitored. Complications, analgesics consumption, duration of the procedure, demographic information, NRS and the Modified Aldrete Score were evaluated. A total remifentanil amount used in Group A was 66.51±47.87 mcg and 90.15±58.17 mcg in Group C (p=0.011); there was no difference in total amounts of ketamine and propofol given. There was a negative correlation between ANI and NRS scores of Group A patients at Minute 0 at the level of 0.402, which was significant statistically (p=0.003). Opioid consumption was diminished when ANI monitoring was used, and thus the patient safety was improved. Further studies with longer procedure times and with a greater number of patients are required to demonstrate whether there is a difference in side effects and recovery times.


New insights into functional roles of the polypyrimidine tract-binding protein.
Polypyrimidine Tract Binding Protein (PTB) is an intensely studied RNA binding protein involved in several post-transcriptional regulatory events of gene expression. Initially described as a pre-mRNA splicing regulator, PTB is now widely accepted as a multifunctional protein shuttling between nucleus and cytoplasm. Accordingly, PTB can interact with selected RNA targets, structural elements and proteins. There is increasing evidence that PTB and its paralog PTBP2 play a major role as repressors of alternatively spliced exons, whose transcription is tissue-regulated. In addition to alternative splicing, PTB is involved in almost all steps of mRNA metabolism, including polyadenylation, mRNA stability and initiation of protein translation. Furthermore, it is well established that PTB recruitment in internal ribosome entry site (IRES) activates the translation of picornaviral and cellular proteins. Detailed studies of the structural properties of PTB have contributed to our understanding of the mechanism of RNA binding by RNA Recognition Motif (RRM) domains. In the present review, we will describe the structural properties of PTB, its paralogs and co-factors, the role in post-transcriptional regulation and actions in cell differentiation and pathogenesis. Defining the multifunctional roles of PTB will contribute to the understanding of key regulatory events in gene expression.


Medical school choice: what influences applicants?
Little is known about factors influencing applicants' choice of medical school, yet it is important that both the academic and non-academic needs of medical students are satisfied, and that medical schools attract students suited to the courses provided. Relevant evidence suggests that there are five main factors influencing choice: curriculum; reputation of the school; personal contact; location; and facilities. Aberdeen has the particular challenge of being the most northern medical school in the UK. To address this challenge, and learning from the literature, a medical school open day was developed to showcase the medical school, the wider university and the city of Aberdeen. The main messages from this small study were that interactive events were more popular than static displays, and that applicants preferred to interact with student representatives rather than just hear about student life, suggesting that the opportunity to ask questions and hear the 'uncensored' version of what being a student is like are important. There are some generalisable messages about what prospective students want from an open day, which along with the prospectus and the website can contribute to informing choice. Further work is needed to identify what is critical in terms of first point of contact, and how much this influences the choice of medical school.


Oxidative proteome alterations during skeletal muscle ageing.
Sarcopenia corresponds to the degenerative loss of skeletal muscle mass, quality, and strength associated with ageing and leads to a progressive impairment of mobility and quality of life. However, the cellular and molecular mechanisms involved in this process are not completely understood. A hallmark of cellular and tissular ageing is the accumulation of oxidatively modified (carbonylated) proteins, leading to a decreased quality of the cellular proteome that could directly impact on normal cellular functions. Although increased oxidative stress has been reported during skeletal muscle ageing, the oxidized protein targets, also referred as to the 'oxi-proteome' or 'carbonylome', have not been characterized yet. To better understand the mechanisms by which these damaged proteins build up and potentially affect muscle function, proteins targeted by these modifications have been identified in human rectus abdominis muscle obtained from young and old healthy donors using a bi-dimensional gel electrophoresis-based proteomic approach coupled with immunodetection of carbonylated proteins. Among evidenced protein spots, 17 were found as increased carbonylated in biopsies from old donors comparing to young counterparts. These proteins are involved in key cellular functions such as cellular morphology and transport, muscle contraction and energy metabolism. Importantly, impairment of these pathways has been described in skeletal muscle during ageing. Functional decline of these proteins due to irreversible oxidation may therefore impact directly on the above-mentioned pathways, hence contributing to the generation of the sarcopenic phenotype.


Violence victimization among Finnish university students: prevalence, symptoms and healthcare usage.
The present study examined the prevalence of various forms of violence victimization among university students in Finland. Violence victimization was analyzed in relation to physical and mental health symptoms, and the use of student healthcare services. A cross-sectional Student Health Survey was performed as a national postal survey for Finnish university students in 2004. In the next phase of the study, an additional postal survey regarding violence victimization was sent to those who had answered the original survey, which resulted in a sample of 905 students. It was found that violence victimization and violence-related health issues were markedly prevalent among Finnish university students. The students reported multiple forms of violence and injury demonstrating the diversity of violence victimization. Male and female victims differed both in the amount and type of symptoms, and in their relationship to the abuser/offender. Violence victimization and gender had a significant main effect on specific symptoms, while no interaction effect was found. The data also showed that violence victimization is overrepresented among frequent healthcare users. These findings have implications for clinical practice and public policy. The present findings provide useful information for policy makers and healthcare professionals concerning the health effects of violence in accordance with the use of healthcare services. More specifically, this information should be taken into consideration when planning student healthcare and could serve as a guideline for student healthcare management.


Reference values for CD4+ and CD8+ T lymphocytes with naïve or memory phenotype and their association with mortality in the elderly.
Well-established reference values which take into account the influence of age on immune cell phenotype, and the impact of naïve or memory T cells on mortality have not been well defined in the elderly. The aim of this study was to evaluate the reference values for the peripheral number of total and naïve or memory CD4 and CD8 T cells in a healthy population in Italy, and to analyze whether the immune phenotype was associated with an increased risk of death among older adults. The number of total or naïve and memory CD4+ or CD8+ T cells was evaluated in the peripheral blood of 288 healthy people ranging in age from 20 to 107 years. Furthermore, to correlate peripheral immune phenotype with mortality rate after a 3-years follow-up, a retrospective analysis was performed on the results from those individuals aged >65 years at the time of the enrollment in the study. The absolute number of total and naïve T cells was progressively reduced with increasing age in both the CD4+ and CD8+ T cell populations. The decrease was particularly evident for cells with naïve phenotype, since CD4-naïve and CD8-naïve T cells respectively showed a 4- and a 2- to 3-fold reduction in 70- to >90-year-old subjects in comparison with young adults. The number of CD4 memory T cells significantly increased with age. No significant age-related change was observed in the number of CD8+ memory T cells. Of the 194 subjects included in the study of association of immune phenotype with mortality, 121 were alive and 73 deceased during the 3-year follow-up. The impact of immune parameters on survival demonstrated that only the absolute number of CD8 memory T cells, after adjustment for age, correlated with increased mortality (OR 1.007, 95% CI 1.002-1.012, p = 0.01). The correlation was significant in female but not in male subjects. We provide reference values for total and naïve or memory CD4 and CD8 T cell populations, and demonstrate that the absolute number of CD8 memory T cells, after adjustment for age, correlates with increased mortality.


[Specific immunotherapy in inhalative allergy to rat epithelium].
The only causal treatment that can be offered to allergic patients apart from allergen avoidance is specific immunotherapy. Its efficacy depends on the specific allergen the patient is allergic to, the quality of the extract, the total amount of allergen administered to the patient and the administration schedule. Our patient suffered from inhalative allergy to rat epithelium with severe rhinoconjunctivitis and bronchial asthma. She regularly worked with laboratory rats as a biologist. A job-shift was impossible for the patient, and so was allergen avoidance. We therefore decided to treat the patient with specific immunotherapy. Treatment was performed as in-patient procedure with Rush-Immunotherapy in dosage increase phase. Maintenance injections were administered as out-patient. As early as some months after induction of the therapy, the patient felt subjective symptom relief, blood samples taken revealed decrease of total IgE and specific IgE towards rat epithelium. Therapy was continued for 18 months, specific IgE against rat epithelium could not be detected any more. The patient does not claim any allergy symptoms when working in the rat laboratory any more. Even in unusual allergies, specific immunotherapy can be indicated. In our patient, specific immunotherapy to rat epithelium lead to complete symptom relief and enabled the patient to practise her profession without restraints.


[A novel binary vector to get marker-free transgenic plant].
A novel practical binary vector to get marker-free transgenic plant was constructed. The estrogen-inducible Cre/loxP DNA recombination system was adopted in this system. All non-target genes located between two identical orientation loxP sites could be excised from the transgenic genome by the Cre expression. In order to analyze this system, the target gene, GUS expression box (CaMV35s: :GUS), was inserted in the MCS outside the region franked by two loxP sites. Then it was introduced into the tobaccos. Results showed that the high-efficiency DNA recombination had take place and the target gene was working order after DNA excitation.


Overdistraction of cervical spinal injuries?
Skeletal traction using skull tongs is an effective standard method of treating cervical vertebral fractures and dislocations. The effects of such traction on the cervical spine are unpredictable, since the degree of soft-tissue damage associated with bony injury varies and therefore cannot be accurately assessed. Traction is potentially harmful to the injured spinal cord. The importance of careful evaluation of the subtle radiological signs of cervical soft-tissue injury, and close radiographic monitoring of patients undergoing skeletal traction, are stressed.


Neuraxial and Combined Neuraxial/General Anesthesia Compared to General Anesthesia for Major Truncal and Lower Limb Surgery: A Systematic Review and Meta-analysis.
Neuraxial anesthesia may improve perioperative outcomes when compared to general anesthesia; however, this is controversial. We performed a systematic review and meta-analysis using randomized controlled trials and population-based observational studies identified in MEDLINE, PubMed, and EMBASE from 2010 to May 31, 2016. Studies were included for adult patients undergoing major surgery of the trunk and lower extremity that reported: 30-day mortality (primary outcome), cardiopulmonary morbidity, surgical site infection, thromboembolic events, blood transfusion, and resource use. Perioperative outcomes were compared with general anesthesia for the following subgroups: combined neuraxial-general anesthesia and neuraxial anesthesia alone. Odds ratios (ORs) and 99% confidence intervals (CIs) were calculated to identify the impact of anesthetic technique on outcomes. Twenty-seven observational studies and 11 randomized control trials were identified. This analysis comprises 1,082,965 records from observational studies or databases and 1134 patients from randomized controlled trials. There was no difference in 30-day mortality identified when combined neuraxial-general anesthesia was compared with general anesthesia (OR 0.88; 99% CI, 0.77-1.01), or when neuraxial anesthesia was compared with general anesthesia (OR 0.98; 99% CI, 0.92-1.04). When combined neuraxial-general anesthesia was compared with general anesthesia, combined neuraxial-general anesthesia was associated with a reduced odds of pulmonary complication (OR 0.84; 99% CI, 0.79-0.88), surgical site infection (OR 0.93; 99% CI, 0.88-0.98), blood transfusion (OR 0.90; 99% CI, 0.87-0.93), thromboembolic events (OR 0.84; 99% CI, 0.73-0.98), length of stay (mean difference -0.16 days; 99% CI, -0.17 to -0.15), and intensive care unit admission (OR 0.77; 99% CI, 0.73-0.81). For the combined neuraxial-general anesthesia subgroup, there were increased odds of myocardial infarction (OR 1.18; 99% CI, 1.01-1.37). There was no difference identified in the odds of pneumonia (OR 0.94; 99% CI, 0.87-1.02) or cardiac complications (OR 1.04; 99% CI, 1.00-1.09) for the combined neuraxial-general anesthesia subgroup. When neuraxial anesthesia was compared to general anesthesia, there was a decreased odds of any pulmonary complication (OR 0.38; 99% CI, 0.36-0.40), surgical site infection (OR 0.76; 99% CI, 0.71-0.82), blood transfusion (OR 0.85; 99% CI, 0.82-0.88), thromboembolic events (OR 0.79; 99% CI, 0.68-0.91), length of stay (mean difference -0.29 days; 99% CI, -0.29 to -0.28), and intensive care unit admission (OR 0.50; 99% CI, 0.48-0.53). There was no difference in the odds of cardiac complications (OR 0.99; 99% CI, 0.94-1.03), myocardial infarction (OR 0.91; 99% CI, 0.81-1.02), or pneumonia (OR 0.92; 99% CI, 0.84-1.01). Randomized control trials revealed no difference in requirement for blood transfusion (RR 1.05; 99% CI, 0.65-1.71) and a decreased length of stay (mean difference -0.15 days; 99% CI, -0.27 to -0.04). Neuraxial anesthesia when combined with general anesthesia or when used alone was not associated with decreased 30-day mortality. Neuraxial anesthesia may improve pulmonary outcomes and reduce resource use when compared with general anesthesia. However, because observational studies were included in this analysis, there is a risk of residual confounding and therefore these results should be interpreted with caution.


Expression and function of NOD-like receptors by human term gestation-associated tissues.
Nucleotide-binding oligomerization domain (NOD)-like receptors or NOD-like receptors (NLRs) have been implicated in several disease pathologies associated with inflammation. Since local and systemic inflammation is a hallmark of both term and preterm labour, a role for NLRs at the materno-fetal interface has been postulated. Gene expression and immunolocalisation of NLR family members in human placenta, choriodecidua, and amnion were examined. Tissue explants were used to examine the response to activators of NOD1 (Tri-DAP), NOD2 (MDP) and NLRP3 (nigericin). Cell/tissue-free supernatants were examined for the production of interleukin (IL)-1β, IL-6, IL-8 and IL-10 using specific ELISAs. Expression of transcripts for NOD1, NOD2, NLRP3, NLRC4, NLRX1, NLRP1 and NAIP and protein expression of NOD1, NOD2 and NLRP3 were a broad feature of all term gestation-associated tissues. Production of cytokines was increased significantly in response to all ligands in placenta and choriodecidua, except for MDP-induced IL-10. Similarly, there was a significant in the amnion except for MDP induced IL-1β and IL-10 response to either agonist. IL-1β production was dependent on caspase-1 regardless of agonist used or tissue examined. Term human gestation-associated tissues express functional NLRs which likely play a role in both sterile and pathogen-driven inflammatory responses at the materno-fetal interface.


Work-Family Conflict and Well-Being among German Couples: A Longitudinal and Dyadic Approach.
This study examines dual-earner couples to determine whether changes in work-family conflict predict changes in one's own (i.e., actor effects) or partner's (i.e., partner effects) health and well-being as well as gender differences in these relationships. Using data from 1,001 dual-earner couples in Wave 6 and Wave 8 of the German Family Panel survey (Pairfam), we found (1) significant actor effects for all outcomes, with stronger actor effects among men than women on mental health; (2) significant partner effects for life satisfaction and mental health, with stronger partner effects among men than women on life satisfaction; and (3) stronger actor effects than corresponding partner effects for life satisfaction and mental health. As work-family conflict has become a fact of life for many contemporary workers, our results contribute by highlighting the importance of using couple-level data and testing longitudinal crossover effects to provide a fuller understanding of such conflict's health consequences.


Four-segmented Rift Valley fever virus induces sterile immunity in sheep after a single vaccination.
Rift Valley fever virus (RVFV), a mosquito-borne virus in the Bunyaviridae family, causes recurrent outbreaks with severe disease in ruminants and occasionally humans. The virus comprises a segmented genome consisting of a small (S), medium (M) and large (L) RNA segment of negative polarity. The M-segment encodes a glycoprotein precursor (GPC) protein that is co-translationally cleaved into Gn and Gc, which are required for virus entry and fusion. Recently we developed a four-segmented RVFV (RVFV-4s) by splitting the M-genome segment, and used this virus to study RVFV genome packaging. Here we evaluated the potential of a RVFV-4s variant lacking the NSs gene (4s-ΔNSs) to induce protective immunity in sheep. Groups of seven lambs were either mock-vaccinated or vaccinated with 10(5) or 10(6) tissue culture infective dose (TCID50) of 4s-ΔNSs via the intramuscular (IM) or subcutaneous (SC) route. Three weeks post-vaccination all lambs were challenged with wild-type RVFV. Mock-vaccinated lambs developed high fever and high viremia within 2 days post-challenge and three animals eventually succumbed to the infection. In contrast, none of the 4s-ΔNSs vaccinated animals developed clinical signs during the course of the experiment. Vaccination with 10(5) TCID50 via the IM route provided sterile immunity, whereas a 10(6) dose was required to induce sterile immunity via SC vaccination. Protection was strongly correlated with the presence of RVFV neutralizing antibodies. This study shows that 4s-ΔNSs is able to induce sterile immunity in the natural target species after a single vaccination, preferably administrated via the IM route.


Antibodies to sperm in benign and malignant diseases of the prostate in man: incidence, disease-associated specificity, and implications.
Initial investigation demonstrated antibodies to sperm (ASA) in patients with benign prostatic hypertrophy (BPH) and prostate cancer (PCa). The occurrence of ASA under a variety of normal and pathological circumstances indicated the need for confirmation and extension, including delineation of their possible disease-associated specificity and implications. As countercurrent immunoelectrophoresis (CIEP) employing sonicated allogeneic sperm (Sp) extracts appeared most efficient from initial studies of ASA, CIEP was employed for the present further study of 200 serum specimens from patients with and without prostatic disease. While ubiquitous, the continuing presence of ASA in BPH and PCa, with a combined incidence in this study of 57 (52%) of 109 vs. 9 (10%) of 91 in the absence of prostatic disease remains provocative in view of the hypothesized role of Sp in the development of BPH and PCa. The presence, however, of ASA in patients with genitourinary neoplasms other than prostate, raises doubt as to their disease specificity. Implications of ASA, other than in their more commonly related role in infertility, including their cross-reactivity with foetal antigens and lymphocytes and higher incidence in association with tumours and the presence of tumour-associated immunity are considered. However, pending further investigation, the present data may most appropriately be viewed as being reflective of a host response (marker?) to aberrant genitourinary cellular alterations.


Pulmonary Kaposi's sarcoma in pregnancy.
Kaposi's sarcoma in human immunodeficiency virus (HIV) -infected women, often misdiagnosed, has an aggressive clinical course, with high rates of visceral involvement and decreased survival. We describe the first case of isolated pulmonary Kaposi's sarcoma in pregnancy. A nulliparous woman was diagnosed with AIDS after presenting at 25 weeks gestation with a cough and multiple pulmonary nodules. Extensive pulmonary evaluation was nondiagnostic until thorascopic lung biopsy revealed Kaposi's sarcoma. Despite combination antiretroviral therapy, her malignancy progressed. Labor was induced at 33.5 weeks gestation for nonreassuring fetal testing. She received chemotherapy postpartum and remains in remission. Pulmonary Kaposi's sarcoma should be considered in the differential diagnosis of HIV-infected obstetric patients with respiratory compromise. Definitive diagnosis is necessary given the aggressive clinical course that is potentially responsive to therapy.


Prolactin as a regulator of fluid and electrolyte metabolism in mammals.
The evidence that prolactin is a fluid and electrolyte regulator in mammals is reviewed, with particular emphasis on the renal actions of prolactin. Prolactin receptors are found in mammalian kidneys. Prolactin modulates renal formation of cyclic AMP and polyamines and it leads to demonstrable histological changes in the proximal tubules. The renal actions of prolactin primarily involve modulation of the effects of other hormones and are therefore critically dependent on the background physiological situation. Prolactin seems able to cause a prolonged reduction in water, sodium, and potassium excretion, a pattern that is imitated by no other hormone with the possible exception of growth hormone. Prolactin preparations can cause an acute antidiuresis, which may in part be related to contamination of prolactin preparations with vasopressin. However, most of the described effects cannot be explained by vasopressin contamination. This is particularly so with the effects of prolactin on water movements across fetal skin, the amniotic membrane, and in the eye where prolactin and vasopressin have diametrically opposite effects. It is concluded that prolactin is a regulator of fluid and electrolyte metabolism in mammals but that it is a modulator rather than a primary controlling factor.


[Isolation and study of active peptides in Salmonella H antigens].
The monomer forms of Salmonella H-antigens a, b, d, i, 1, 2 have both specific antigenic determinants, characteristic of each H-antigen, and common determinants. The presence of two types of determinant groups leads to the appearance of cross reactions in the enzyme immunoassay. In this work the method for the isolation of peptides carrying only specific antigenic determinants is proposed.


Changes in organelle position and epithelial architecture associated with loss of CrebA.
Drosophila CrebA facilitates high-level secretion by transcriptional upregulation of the protein components of the core secretory machinery. In CrebA mutant embryos, both salivary gland (SG) morphology and epidermal cuticle secretion are abnormal, phenotypes similar to those observed with mutations in core secretory pathway component genes. Here, we examine the cellular defects associated with CrebA loss in the SG epithelium. Apically localized secretory vesicles are smaller and less abundant, consistent with overall reductions in secretion. Unexpectedly, global mislocalization of cellular organelles and excess membrane accumulation in the septate junctions (SJs) are also observed. Whereas mutations in core secretory pathway genes lead to organelle localization defects similar to those of CrebA mutants, they have no effect on SJ-associated membrane. Mutations in tetraspanin genes, which are normally repressed by CrebA, have mild defects in SJ morphology that are rescued by simultaneous CrebA loss. Correspondingly, removal of several tetraspanins gives partial rescue of the CrebA SJ phenotype, supporting a role for tetraspanins in SJ organization.


Transverse tubular system depolarization reduces tetanic force in rat skeletal muscle fibers by impairing action potential repriming.
When muscle fibers are repeatedly stimulated, they may become depolarized and force output decline. Excitation of the transverse tubular system (T-system) is critical for activation, but its role in muscle fatigue is poorly understood. Here, mechanically skinned fibers from rat fast-twitch muscle were used, because the sarcolemma is absent but the T-system retains normal excitability and its properties can be studied in isolation. The T-system membrane was fully polarized by bathing the skinned fiber in an internal solution with 126 mM K(+) (control solution) or set at partially depolarized levels (approximately -63 and -58 mV) in solutions with 66 or 55 mM K(+), respectively, and action potentials (APs) were triggered in the sealed T-system by field stimulation. Prolonged depolarization of the T-system reduced tetanic force proportionately more than twitch force, with greater effect at higher stimulation frequency (responses at 20 and 100 Hz reduced to 71 and 62% in 66 mM K(+) and to 54 and 35% in 55 mM K(+), respectively). Double-pulse stimulation showed that depolarization increased the repriming period (estimated minimum time before a second AP can be produced) from approximately 4 ms to approximately 7.5 and 15 ms in the 66 and 55 mM K(+) solutions, respectively. These results demonstrate that T-system depolarization reduces tetanic force by impairing AP repriming, rather than by preventing AP generation per se or by inactivating the T-system voltage sensors. The findings also explain why it is advantageous to reduce the rate of motoneuron stimulation to muscles during repeated or prolonged periods of activity.


Pharmacologic treatment of acute renal failure in sepsis.
The pathophysiology of acute renal failure in sepsis is complex and includes intrarenal vasoconstriction, infiltration of inflammatory cells in the renal parenchyma, intraglomerular thrombosis, and obstruction of tubuli with necrotic cells and debris. Attempts to interfere pharmacologically with these dysfunctional pathways, including inhibition of inflammatory mediators, improvement of renal hemodynamics by amplifying vasodilator mechanisms and blocking vasoconstrictor mechanisms, and administration of growth factors to accelerate renal recovery, have yielded disappointing results in clinical trials. Interruption of leukocyte recruitment is a potential promising approach in the treatment of septic acute renal failure, but no data in humans are presently available. Activated protein C and steroid replacement therapy have been shown to reduce mortality in patients with sepsis and are now accepted adjunctive treatment options for sepsis in general.


Effects of the diabetic condition on grafted fat survival: an experimental study using streptozotocin-induced diabetic rats.
Autologous fat grafts have been widely used for cosmetic purposes and for soft tissue contour reconstruction. Because diabetes mellitus is one of the major chronic diseases in nearly every country, the requirement for fat grafts in diabetes patients is expected to increase continuously. However, the circulation complications of diabetes are serious and have been shown to involve microvascular problems, impairing ischemia-driven neovascularization in particular. After injection, revascularization is vital to the survival of the grafted fat. In this study, the authors attempted to determine whether the diabetic condition inhibits the survival of injected fat due to impaired neovascularization. The rat scalp was used for testing fat graft survival. Forty-four seven-week-old male Sprague-Dawley rats were allocated to a diabetic group or a control group. 1.0 mL of processed fat was injected subcutaneously into the scalp of each rat. The effect of diabetes was evaluated by calculating the volume and the weight of the grafted fat and by histologically analyzing the fat sections. The surviving fat graft volume and weight were considerably smaller in the diabetic group than in the control group (P<0.05), and histological evaluations showed less vascularity, and more cysts, vacuoles, and fibrosis in the diabetic group (P<0.05). Cellular integrity and inflammation were not considerably different in the two groups. As the final outcome, we found that the presence of diabetes might impair the survival and the quality of fat grafts, as evidenced by lower fat graft weights and volumes and poor histologic graft quality.


Imaging memory and predicting postoperative memory decline in temporal lobe epilepsy: Insights from functional imaging.
After medial temporal lobe epilepsy (MTLE) surgery, there is considerable individual variation in the extent, nature and direction of postoperative memory change. Before surgery, epileptic patients who are surgery candidates need precise information about the potential cognitive after effects, and particularly in temporal lobe epilepsy, postoperative memory changes. Clinical and neuropsychological data may bring useful information to predict the postoperative memory outcome, but, these data are not always sufficient to replace the Wada test, considered for a long time, as the gold standard to predict postoperative decline following surgery. In any case, numerous studies demonstrate that the Wada procedure can be nowadays reliably replaced by functional MRI (fMRI) activation studies. A vast majority of fMRI studies suggest that it is the functional adequacy of the resected hippocampus rather than the functional reserve of the contralateral hippocampus that determines the extent of postoperative memory decline. In addition, new functional neuroimaging procedures that explore more widespread network disruptions commonly found in MTLE such as diffusion-tensor imaging (DTI) or connectivity studies could in the future constitute a reliable approach combined with fMRI activation studies to significantly improve the prediction of postsurgical memory decline.


Human umbilical cord perivascular cells exhibited enhanced migration capacity towards hepatocellular carcinoma in comparison with bone marrow mesenchymal stromal cells: a role for autocrine motility factor receptor.
Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. Unfortunately, the incidence and mortality associated with HCC are increasing. Therefore, new therapeutic strategies are urgently needed and the use of mesenchymal stromal cells (MSCs) as carrier of therapeutic genes is emerging as a promising option. Different sources of MSCs are being studied for cell therapy and bone marrow-derived cells are the most extensively explored; however, birth associated-tissues represent a very promising source. The aim of this work was to compare the in vitro and in vivo migration capacity between bone marrow MSCs (BM-MSCs) and human umbilical cord perivascular cells (HUCPVCs) towards HCC. We observed that HUCPVCs presented higher in vitro and in vivo migration towards factors released by HCC. The expression of autocrine motility factor (AMF) receptor, genes related with the availability of the receptor on the cell surface (caveolin-1 and -2) and metalloproteinase 3, induced by the receptor activation and important for cell migration, was increased in HUCPVCs. The chemotactic response towards recombinant AMF was increased in HUCPVCs compared to BM-MSCs, and its inhibition in the conditioned medium from HCC induced higher decrease in HUCPVC migration than in BM-MSC. Our results indicate that HUCPVCs could be a useful cellular source to deliver therapeutic genes to HCC.